- BioRxiv Biochemistry
- BioRxiv Bioinformatics
- BioRxiv Biophysics
- BioRxiv Cancer Biology
- BioRxiv Pharmacology and Toxicology
- BioRxiv Systems Biology
- BioRxiv Zoology
- by Bailly, T. P. M., Lamers, S. J. C., Sarma, A., Jansen, A. C. M., Freerks, K., van Dijk, M., Etienne, R. S., Wertheim, B., Billeter, J.-C.Sociability, the propensity of an individual to engage in group activities, is a trait present in all social species. In humans and many animals, sociability varies between individuals yet remains consistent across contexts, qualifying it as a personality trait. Sociability influences health and physiology, but the mechanisms underlying sociability and its inter-individual variation remain poorly understood. The genetically tractable fruit fly, Drosophila melanogaster, is increasingly used to study social behavior and exhibits a wide range of sociability phenotypes. However, previous […]
- by Clarke, S. E., Percival, C. C., Pennycuick, A., Whiteman, Z. E., Ishii, Y., Gomez-Lopez, S., Rouhani, M. J., Alhendi, A., Orr, J. C., Selway-Clarke, H., El-Mdawar, M.-B., Hagel, Z. C., Otter, K. E., Khaw, C. R., Hall, H., Bhamani, A., Hynds, R. E., Gowers, K. H. C., Janes, S. M.Basal cells are key to maintaining and repairing a functioning airway epithelium. Understanding how basal cells maintain normal airways provides a foundation for interpreting their dysfunction in disease states and for the development of novel therapies. The airway epithelium exists in a dynamic state in which basal stem cells replace lost luminal mucosecretory and multiciliated cell types via an intermediate suprabasal cell state. The ability to isolate basal cells with high progenitor cell potential would be beneficial in regenerative medicine […]
- by Li, F., Wu, X., Xie, Y., Yang, J., Xi, J., Sun, Y., Chen, J., Wu, X., Huang, S., Zhang, C., Zheng, Y., Li, W., Zuo, X., Li, Y., Chen, K., Lai, X., Liu, X., Zhong, W., Zeng, J., Wu, Q., Garcia, B., Lu, H., Xia, H., Zhou, W., Zhang, Y.Glycans modify nucleic acids, proteins and lipids in fundamental biological processes, but have long been considered confined to the secretory pathway and cell surface. Here, we challenge this view with evidence that N-glycosylation, a ubiquitous glycan modification, occurs within cell nuclei across tissues and species, exhibiting cell type-dependent abundance and localization patterns. Using a multi-faceted approach, we show that numerous classical membrane and secreted glycoproteins localize to the nucleus with N-glycan modifications, exemplified by the cell adhesion molecule L1CAM. Mechanistically, […]
- by KIM, C. H., Zhu, Z., Tagmount, A., Barbazuk, W. B., Bacher, R., Vulpe, C. D.Many omics-based approaches in toxicology research primarily rely on correlative data, often lacking functional relationships or causal links between genotypes and phenotypes. CRISPR-based approaches can overcome this limitation by establishing direct causal connections between genes and toxicological phenotypes. Moreover, CRISPR screens enable scalable and systematic interrogation of gene function and associated mechanisms following chemical exposure, predominantly using in vitro models. In line with the paradigm of new approach methodologies (NAMs) in toxicology research, CRISPR screens hold promise to provide an […]
- by Becquart, P., Tournier, P., Junyent, S., Ma, B., Liu, Y., Tang, Y., Chen, X., Fang, D., Kusumbe, A., Habib, S. J.Engineering functional tissues for transplantation requires insight into epigenetic mechanisms that regulate stem cell fate. We have developed the Wnt-induced osteogenic tissue model (WIOTM), a platform that recapitulates human osteogenesis, and identified acetylation of histone H3 at lysine 14 (H3K14ac) as a critical epigenetic regulator in human skeletal stem cells (hSSCs). In WIOTM, localized Wnt signals drive asymmetric cell division (ACD), yielding a proximal hSSC with high H3K14ac and a distal daughter with reduced H3K14ac that migrates into the 3D […]
- by Matthews Nicholass, K. J., Flis, I., Hanley, M. E., Knight, M. E., Lane, S. M., Littlejohn, G. R., Billington, R. A., Boden, R., Cummins, R., Green, B. J., Griffin, C. D., Jones, S., Salmon, D., Sleep, I., Smirnoff, N., Ellis, J. S.Research into psychedelic compounds is in resurgence due to the exciting potential for their use in the treatment of psychiatric and mental health disorders. Despite this revival, remarkably little is known about their evolution. One of the most intriguing psychedelic compounds is psilocybin, the compound found in 'magic' mushrooms and used in ritual ceremonies in Central America for generations. Associated with agaricomycete fungi of the genus Psilocybe, psilocybin acts in a similar way to the neurotransmitter serotonin, yet how and […]
- by Oliveira, B. S., Paiva, R. A., Pinto, C. C., Paiva, R. V., Pereira, M. X., Ramos, C. V., Azenha, S., Paixao, T., Faisca, P., Martins, V. C.Cell competition in the thymus is a critical tumor suppressor mechanism that prevents leukemia. Here, we show that suboptimal bone marrow correction of {gamma}c-deficient mice triggers thymus autonomy and subsequent T cell acute lymphoblastic leukemia (T-ALL). {gamma}c-deficiency results in severe combined immunodeficiency (SCID) in mice and humans, and correction is achieved by hematopoietic stem and progenitor cell (HSPC) transplantation. Following inefficient bone marrow correction of {gamma}c-deficient mice, thymus function was intermittent, consistent with sporadic thymic colonization events. Thymocyte composition and […]
- by Abel, T. R., Pandey, R. S., Haber, A., Garceau, D., Sasner, M. J., Kotredes, K. P., Cary, G. A., Oblak, A., Howell, G. R., Lamb, B. T., Carter, G. W.INTRODUCTION: TREM2 loss of function variants are associated with late-onset Alzheimer's disease (LOAD). We molecularly assessed mice with the missense variant, R47H (Trem2*R47HHSS), and mice with additional cryptic splicing and reduced Trem2 expression (Trem2*R47H) while comparing relevance to human LOAD. METHODS: The aberrant splice acceptor site in the Trem2*R47H mouse was humanized resulting in the Trem2*R47H humanized splice site (Trem2*R47HHSS) mouse. RNA sequencing was performed on mouse brain tissue and signatures were compared to human postmortem brain expression in LOAD […]
- by Messa, G. M., Liu, P., Napolitano, F., tegner, j., Gao, X., Orlando, V.Circadian metabolism arises from complex, time-dependent interactions across organs, yet experimental characterization in humans remains limited. Current whole-body metabolic models are either too large for dynamic simulation or insufficiently detailed to capture temporal physiology. We developed a multi-tissue human metabolic reconstruction, HGEM1.19+, an extensively curated model for dynamic simulation. We introduced Thermo-Dynamic Flux Balance Analysis (tdFBA), a novel formulation that integrates thermodynamic constraints, organ-specific enzyme capacities, solubility limits, osmotic balance and pH buffering. Murine circadian transcriptomics and metabolomics were integrated […]
- by Mansoori, B., Song, Y., Zhang, T., Zheng, Z., Zhu, Q., Li, S., Reale, M., Pangilinan, C., Machhar, J. S., Liang, J., Chang, J., Hong, Y.-K., Wertheim, G. B., Murphy, M. E., Kim, Y.-M., Muschen, M., Gack, M. U., Kossenkov, A. V., Liu, Q., Auslander, N., Aifantis, I., Parekh, C., Liang, C.Cell surface receptors such as NOTCH1 must be tightly regulated to ensure developmental fidelity and prevent pathological activation. Although the proteolytic steps culminating in nuclear NOTCH1 signaling are established, how cells prevent excessive or uncontrolled activation has remained unresolved. Here we identify the autophagy-related protein UVRAG as a negative regulator of NOTCH1. Upon receptor activation, UVRAG, acting independently of autophagy, recruits and activates the E3-ligase ITCH to catalyze K27-linked ubiquitination of membrane-tethered NOTCH1, thereby licensing ESCRT-dependent lysosomal degradation. Disruption of […]
- by Daouk, R., Cutrupi, F., Liu, P., Mangiavacchi, A., Della Valle, F., Morelli, G., D'Onghia, M., Niksic, A., Huch, M., Orlando, V.Endogenous retroelements such as LINE-1 (L1) are stress-responsive genomic elements increasingly implicated in stress induced inflammation and associated pathogenic states. Here, we uncover a novel mechanism whereby high-fat diet-associated palmitic acid stress triggers chromatin remodeling that derepresses L1 elements and an IRF3-dependent interferon response, leading to innate immune activation in hepatocytes. Mechanistically, we show that that palmitic acid exposure promoted p300/CBP-mediated H3K122 succinylation at L1 promoters, coupled with reduced sirtuin desuccinylase cofactor availability, thereby enhancing chromatin accessibility and transcription. Antisense […]
- by Musheev, M., Schomacher, L., Schott, J. M., Basu, A., Moeckel, M. M., Heinen, S., Frosch, L., Guo, P., Yang, G., Huang, Q., Niehrs, C.Recent evidence indicates that mono- and poly-ADP ribosylation (MARylation and PARylation) are not limited to proteins but extend to DNA. Notably, in vitro base PARylation by PARP1 in single stranded DNA (ssDNA) was demonstrated at N1-deoxyadenosine (N1-dA). Here, we report that PARP1 catalyzes N3-specific ADP-ribosylation of deoxycytidine (N3-dC) in single-stranded DNA. Analogous to N1-dA PARylation, which is prone to spontaneous adenine-to-inosine deamination, N3-dC PARylation promotes cytosine deamination, yielding N3-PARylated-deoxyuridine. These deamination products yield diagnostic PARylation signatures in LC-MS/MS, namely N1-ribosyl-deoxyinosine […]
- by Jain, R. P., Amini, R. R., Korzh, V.Zebrafish hatching, a critical developmental milestone, occurs around 48-72 hours post-fertilization (hpf). It is regulated by the specialized secretory organ called the hatching gland. Voltage-gated potassium channels (Kv) are known for their roles in maintaining plasma membrane potential and regulating intracellular protein traffic and secretion. Previous studies on zebrafish mutants of Kv2.1 channel subunits – the electrically active subunit Kcnb1 and the modulatory subunit Kcng4b – revealed antagonistic functions in the development of brain ventricles, ear, and Reissner fiber. In […]
- by ZUGASTI, O., Royet, J.Larvae of many insects develop immersed in decomposing substrates densely populated with microbes, yet how they detect and respond to pathogenic threats during early life remains poorly understood. Here, we show that Drosophila melanogaster larvae exhibit a previously unrecognized rapid escape behavior triggered by food contaminated with metabolically active Erwinia carotovora carotovora 15 (E. cc15), a natural bacterial pathogen of flies and plants. Stationary-phase cells fail to elicit avoidance, demonstrating that larval detection of E. cc15 depends on bacterial metabolic […]
- by Fu, X., Epting, C. L., Sinha, A., Monge, M. C., Zhao, M., Glinton, K., Krishnan, S. T., Nguyen, M. L. T., Dudley, V. J., Waypa, G. B., Lara, P. G., Kishawi, T., Lantz, C., Winlaw, D. S., Schumacker, P. T., Thorp, E. B., Ge, Z.-D.BACKGROUND: The myocardium in hypoplastic left heart syndrome (HLHS) exhibits immature metabolic programming, impaired mitochondrial quality control, and heightened susceptibility to ischemic and hypoxic injury during palliative surgery. The long non-coding RNA H19 suppresses translation of PTEN-induced putative kinase 1 (PINK1) mRNA and modulates mitochondrial quality control and ischemia/reperfusion injury (IRI) in adult hearts. Whether and how H19 regulates mitophagy and IRI in HLHS or in immature animals remains unknown. METHODS: We investigated H19 regulation and its role in mitophagy […]
- by KIM, C. H., Tagmount, A., Zhu, Z., Wilson, F., Li, D., Ostrov, D., Barbazuk, W. B., Bacher, R., Vulpe, C. D.Perfluorooctane sulfonate (PFOS) poses significant health and environmental risks due to its persistence and widespread use and has been linked to various adverse outcomes, such as liver toxicity. Although the molecular responses and toxicity effects of PFOS exposure have been extensively studied, considerable uncertainty remains regarding the causal mechanisms leading to PFOS-associated adverse effects. To help bridge this gap, we conducted CRISPR screens in HepG2/C3A human liver cells exposed to IC25 (170 uM) of PFOS to identify genes and pathways […]
- by Byrne, I., Popovic, I., Green, R. H., MacDonald, C., Longenecker, J. M., Purkis, S. J., Nunez-Vallecillo, M., Rivera Sosa, A., Rivera, A., Ortega, P., Prata, K. E., Bairos-Novak, K. R., Bachman, S., Pinsky, M., Beger, M., Fox, H. E., Riginos, C.Conserving genetic diversity is crucial for maintaining species' evolutionary potential and resilience to environmental change. Yet, directly measuring genetic diversity across large spatial scales remains resource-intensive and impractical for conservation planning. Identifying reliable, accessible, and cost-effective spatial predictors of genetic diversity would significantly enhance our ability to incorporate genetic diversity into conservation efforts. Caribbean coral reefs represent a compelling system for investigating such predictors, as these ecosystems face unprecedented threats from disease outbreaks and climate change. Here, we investigate the […]
- by Paul, A., Joshi, G., Jungk, P., Kaur, S., Yao, S., Tsirkas, I., Boehly, N., Sitte, M., Salinas, G., Hamperl, S., Kschischo, M., Bastians, H.Cancer chromosomal instability (CIN) drives tumor evolution through generating structural and numerical chromosome aberrations. However, its molecular determinants remain poorly characterized. Here, we uncover a yet unrecognized role for the tumor suppressor SMAD4 as a key regulator of genome stability. Mechanistically, loss of SMAD4 induces replication stress by promoting transcription-replication conflicts (TRCs), which induces chromosomal breaks and subsequent mitotic errors, leading to the concomitant emergence of structural and numerical CIN. While the tumor suppressor function of SMAD4 has been predominantly […]
- by Dai, D., Liao, Y., Bo, D., Siddique, S., Zhou, Y., Hu, B., Zhang, S., Zhang, Y., Zhu, P., Peng, D., Sun, M., Zheng, J.N6-methyladenine (6mA) DNA methylation has emerged as an important epigenetic mark in eukaryotes, but its biological role in plant-parasitic nematodes remains largely unexplored. Here, we demonstrate that 6mA methylation is essential for the embryonic development and parasitic ability of Meloidogyne incognita. Silencing of the 6mA demethylase genes minmad-1 significantly reduced egg hatching, revealing that 6mA-mediated regulation is required for nematode development. Transcriptome analyses showed that minmad-1 knockdown downregulated genes involved in embryogenesis, RNA biosynthesis, and cell differentiation, suggesting a critical […]
- by Jang, Y., Qin, Q.-Q., Wang, J.-L., Kornmann, B.Remarkable progress has been achieved by machine learning, particularly in accurate prediction of protein tertiary structures. Despite these advances, accurately annotating protein functions through machine learning approaches remains challenging, primarily due to the limited availability of large-scale benchmarking data. In this study, we addressed this gap by systematically screening proteins from the UniProt database for functional annotations, resulting in the creation of a benchmarking dataset that includes protein sequences and their corresponding annotations. The Protein Annotation Dataset (PAD) is a […]